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No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas

Nature Genetics volume 40, pages 650–655 (2008)Cite this article

Abstract

There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinoma-promoting phenotypes of breast and ovarian CAFs.

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Figure 1: Examples of manual microdissection from hematoxylin and eosin stained sections.
Figure 2: Genome-wide copy number and LOH analysis plot of different cell types within medullary breast cancer sample P5077.
Figure 3: Genome-wide copy number and LOH analysis plot of different cell types within serous ovarian cancer sample IC131.
Figure 4: Allelic imbalance analysis of chromosome 22 in fibroblast and epithelial foci of ovarian cancer sample IC307.
Figure 5: Genome-wide copy number plots and LOH plot of two primary breast CAFs.
Figure 6: Assessment of allelic imbalance at stroma-specific mutation hot spots in ovarian cancer sample IC293 and breast cancer sample P5077.

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Acknowledgements

We thank the Peter MacCallum Cancer Centre Tissue Bank, and particularly L. Devereux, for their assistance in accessing tumor samples. We also thank the Peter MacCallum Cancer Centre Microarray and Bioinformatics core facilities for their assistance in the SNP array analysis. This work was supported by a grant (ID 400107) from the National Health and Medical Research Council of Australia (NHMRC). W.Q. is supported by NHMRC Dora Lush Postgraduate Scholarship. E.R.T. is supported by National Breast Cancer Foundation Postgraduate Scholarship. M.R. is supported by Melbourne Research Scholarship from University of Melbourne, Australia. I.H. is supported by US Department of Defense WXH1-1-06-0643 and the Komen for the Cure grants. This work was supported in part by US National Institutes of Health (CA116235) and American Cancer Society (RSG-05-154-01-MGO) grants to K.P.

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Authors and Affiliations

  1. VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, 3002, Victoria, Australia

    Wen Qiu, Anita Sridhar, Ella R Thompson, Manasa Ramakrishna, Kylie L Gorringe & Ian G Campbell

  2. Department of Biochemistry, University of Melbourne, Melbourne, 3010, Australia

    Wen Qiu & Izhak Haviv

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Min Hu, Michail Shipitsin & Kornelia Polyak

  4. Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Min Hu, Michail Shipitsin & Kornelia Polyak

  5. Department of Pathology, St Vincent's Hospital, Fitzroy, 3065, Victoria, Australia

    Ken Opeskin

  6. Department of Pathology, University of Melbourne, Melbourne, 3010, Australia

    Ken Opeskin, Ella R Thompson, Manasa Ramakrishna & Ian G Campbell

  7. Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, 3002, Victoria, Australia

    Stephen Fox & Melanie Trivett

  8. Cancer Cell Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, 3002, Victoria, Australia

    Izhak Haviv

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  1. Wen Qiu
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Contributions

I.G.C., I.H. and W.Q. designed the study and wrote the paper. W.Q. undertook the bulk of the experimental work including tissue microdissection, SNP genotyping and microsatellite analysis. K.P. provided cell lines, academic support and assisted in manuscript preparation. A.S., E.R.T., M.R. and K.L.G. assisted in SNP genotyping. M.H. and M.S. provided breast CAF DNA. M.H. undertook expression and promoter methylation analysis. K.O. and S.F. provided pathological review of tissue samples. M.T. performed immunohistochemistry analysis.

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Correspondence to Ian G Campbell.

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Qiu, W., Hu, M., Sridhar, A. et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat Genet 40, 650–655 (2008). https://doi.org/10.1038/ng.117

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